WO2003091645A1

WO2003091645A1 - Freeze-drying device

Info

Publication number: WO2003091645A1
Application number: PCT/EP2003/003893
Authority: WO
Inventors: Bernd Sennhenn; Dietrich Gehrmann; Ariane Firus
Original assignee: Bayer Technology Services Gmbh
Priority date: 2002-04-23
Filing date: 2003-04-15
Publication date: 2003-11-06
Also published as: ATE458973T1; NZ536051A; EP1502063B1; ES2337777T3; JP2005524041A; EP1502063A1; CA2483152A1; US6931754B2; ZA200408489B; KR101026067B1; CN100554842C; CA2483152C; IL164740A0; RU2004134330A; AU2003229670B2; US20040060191A1; DE10218007A1; CN1682083A; MXPA04010416A; KR20040106366A

Abstract

The invention relates to drying equipment for removing solvent from humid material and to a method for operating the drying equipment. The equipment comprises at least one drying chamber (23) comprising at least one support plate (2) for receiving containers (3) filled with humid material or planar layers of humid material. The drying chamber (23) is connected to the capacitor (22) by a vapour channel (15) in which the sublimated solvent can be separated; the support plates (2) are connected to a temperature regulated heating/cooling circuit; the chamber (23) comprises heating/cooling plates (4) or (4') which are connected to a second heat transfer medium circuit. The invention is characterised in that the heating/cooling plates (4) or (4') are configured in such a manner that they can be substantially thermally decoupled from the chamber wall (6).

Description

Freeze dryer

The invention relates to a freeze-drying chamber with coolable / heatable shelves for a large number of product-filled containers or with coolable heatable shelves which can be covered with product layers, with special devices which eliminate the harmful temperature effects of the chamber wall surfaces which depend on the progress of drying. Special designs make it possible to avoid high energy loss through a special chamber wall structure while reducing the mass of the temperature-controlled components

When drying in known freeze drying chambers with a large number of shelves for product-filled containers or flat product layers, the containers or product layers in the edge area of the shelves have a more intensive energy exchange than the containers / product layers positioned in the middle of the plate due to radiant heat exchange and natural convection in the gap between the wall and the stack of shelves , This inhomogeneity of the energy distribution leads to different freezing and drying kinetics when comparing between containers and product layers on the edge and in the middle.

The avoidance of inhomogeneity is achieved by eliminating the driving potential responsible for the irregularities. The driving potential for drying is the temperature difference between product-filled containers or product layers and their surroundings, which provides the potential necessary for freeze-drying to proceed. This potential is greater in the edge area of the shelves than in the middle area of the shelf because direct heat exchange by radiation and convection takes place between containers on the edge and the chamber wall. During the freezing process according to the state of the art (at normal or slightly reduced pressure), the natural convection of the gas acts in the free gap between the wall and the temperature-controlled one

Plates particularly strong as a heat transfer medium for the convection current exposed container. These additional heat flows decrease towards the middle of the plate and thus cause the inhomogeneous freezing and drying process of the containers or product layers distributed over the plate.

According to the state of the art, freeze dryers are manufactured either without a temperature control device for the chamber walls or with heating / cooling jackets that are applied directly to the supporting structure. These heating / cooling jackets have the purpose of cooling the chamber from the sterilization temperature to the temperature suitable for loading because of the short to ground with the heavy supporting structure of the chamber. Thereafter, the coolant is usually emptied from these heating / cooling surfaces in order to reduce mass. The cooling of the chamber wall to a temperature that eliminates the driving potential responsible for the fault is not possible with these designs.

A freeze dryer is described in US Pat. No. 5,398,426, the chamber walls of which can be cooled in order to eliminate the disruptive temperature differences by the same temperatures of the chamber walls and setting plates. This construction has two disadvantages:

1. The additional cooling surfaces are in the mechanical support structure of the

Integrated dryer, which must be sufficiently reinforced for evacuation. This has the disadvantage of having to heat / cool large masses during operation of the dryer. Therefore, the dryer necessarily reacts thermally slow.

2. The regulation according to US-A-5 398 426, namely the equality of wall and shelf temperature, does not lead to the desired elimination of the driving potential responsible for the disturbance and therefore not to elimination, especially during the first drying section, sublimation drying of inhomogeneities especially during the

Sublimation. The invention is therefore based on the following objects:

• Eliminate the non-uniformity between the edge and center area of the shelves, which freezes and dries product-filled

Containers leads to uneven temperature and drying profiles of the containers;

• Reduction of the heatable or coolable mass of the dryer.

The unevenness is eliminated by regulated heating / cooling plates, which are set so that there is no driving temperature gradient between the wall and the containers. The homogeneity of the freezing and drying process of all containers enables the uniformity of the product quality to be improved and the drying capacity to be increased considerably.

The driving potential responsible for the fault is eliminated by means of additional temperature-controlled heating / cooling surfaces which are introduced into the drying chamber. These heating / cooling surfaces can be arranged differently. Remaining natural convection - as e.g. between containers or product layers and shelves - is minimized by additional pressure reduction during the freeze section of freeze drying.

The invention relates to a drying apparatus for removing solvent from moist material, consisting of at least one drying chamber with at least one positioning plate for receiving containers or flat layers of moist material filled with moist material, the drying chamber being connected to a condenser via a vapor channel which the sublimed solvent can be separated off, the setting plates being connected to a temperature-controlled heating / cooling circuit, the chamber having heating / cooling plates or which are connected to a second heat transfer circuit, characterized in that that the heating / cooling plates are largely thermally decoupled from the chamber wall.

The unevenness is eliminated by regulated heating / cooling plates, which are set so that there is no driving temperature gradient between

Wall and containers prevail. The homogeneity of the freezing and drying process of all containers enables the uniformity of the product quality to be improved and the drying capacity to be increased considerably.

To enable temperature control, the shelves can be used with a

Piping system should be provided. A current of temperature-controlled heat transfer medium flows through the piping system, which is supplied from a heating / cooling system.

A preferred drying apparatus is characterized in that the heating / cooling plates are arranged or spaced from the chamber wall.

The outer chamber wall is particularly preferably designed to be pressure-resistant, so that the surface forces are absorbed without deformation when the chamber is evacuated.

A drying apparatus is also preferred in which the outer chamber wall has thermal insulation so that the energy loss of the system is minimized.

Also preferred is a drying apparatus in which the heating / cooling plates are connected in a vacuum-tight manner to the chamber wall, so that a two-chamber system is effectively obtained.

The heating / cooling surfaces are connected in particular via spacers with the inner surface of the chamber wall mechanically ^'and form therewith an evacuable flat gap. Here vacuum connections are provided in the chamber wall. A drying apparatus is also preferred, characterized in that the gap can be adjusted to the pressure level of the drying chamber by a vacuum system for the purpose of pressure equalization.

The spacers are preferably made of poorly heat-conducting material, in particular stainless steel.

A special version of the drying apparatus is characterized in that elastic connecting plates between the side heating / cooling plates and the

Chamber wall must be designed so flexibly that the temperature-related changes in length of the heating / cooling surfaces can be compensated for without material damage.

In a preferred further embodiment of the drying apparatus

Heating / cooling plates are hung parallel to the edges of the positioning plates at a distance from the positioning plates in the drying chamber, so that the hanging heating / cooling plates form an almost closed radiation cage around the stack of positioning plates

In a preferred further embodiment of the drying apparatus, the drying chamber is already evacuated during the freezing process in order to reduce the effects of convection

In a special design, the chamber wall has external thermal insulation.

In a preferred drying apparatus, the facilities for CLP / SIP are installed in such a way that all surfaces can be cleaned. A drying apparatus is preferred, characterized in that the temperature control systems for the heating / cooling plates can be set to the suitable temperature in a sensor-controlled manner.

In a variant of the preferred drying apparatus, the temperature control systems for the heating / cooling plates are predictively controlled to the appropriate temperature by a computer program.

In a further preferred variant of the drying apparatus, the temperature control systems for the heating / cooling plates are made up of a hybrid system consisting of sensor and

Computer controlled and set to the appropriate temperature.

With the arrangement of the heating / cooling plates according to the invention, the same mass ratios between the heating / cooling plates and the setting plates are produced, thus enabling approximately the same temperature / time profiles for walls and setting plates / containers.

The control of the heating / cooling plates follows the following strategy:

Due to the temperature equality of walls and only shelves (as in US

A-5,398,426) this disturbance can be reduced but not eliminated. Rather, the wall temperatures during freeze-drying essentially have to be tracked to the vial temperature (FIG. 3.b) in order to eliminate the disturbances almost completely. This effect is achieved by eliminating the annoying temperature difference between the chamber wall and the container / shelf.

The container and the shelf are not at the same temperature during the first drying section, so that a mixed temperature of the container and the shelf temperature must be set for the wall temperature. This mixing temperature is expediently determined with the aid of a simulation program on the basis of a predefined lyocycle (temperature, pressure and time profile). The solution to this problem is achieved by installing the separately temperature-controlled heating / cooling surfaces that surround the shelves on all four sides, so that an almost closed radiation cage is created. By eliminating the temperature differences between the heating / cooling plates and the shelf / container, the formation of the annoying free convection with its heat supply to the containers standing on the edge or the product layer at the edge of the plate - especially during the freezing step (here the free convection is effective particularly strong at ambient pressure) - prevented. In contrast, during freeze drying at low system pressures, free convection plays a rather subordinate role.

The regulation / control of the heating / cooling plate temperature can be carried out according to the following strategies:

Sensor-controlled control: During the freezing phase, the shelves and

Heating / cooling plates regulated according to the same temperature program. After starting the drying program, the heating / cooling plate temperature and the shelf temperature follow different programs. The shelf temperature is determined by the specified lyocycle and the temperature / time program specified in the lyocycle is run and regulated. The temperature of the heating-Z cooling plates is set in the first drying section to the sublimation temperature of the frozen product, which is dependent on the chamber pressure and on the solvent. In a first approximation, this temperature can be calculated on the basis of the material values. Measurements of the sublimation temperature in the laboratory can be used to correct this calculated temperature.

The pressure increase method for the direct determination of the sublimation temperature can also be used, e.g. by G.W. Oetjen in "Freeze drying", VCH Verlag, 1997 is described.

The temperature of the heating / cooling plates must be changed when the second

Dry section begins. The beginning of the second drying section can be detected are measured by measuring the system pressure in the gas flow from the freezer with different pressure measuring probes, e.g. an absolute pressure measuring device and a conductivity probe (e.g. Pirani probe), which is set to nitrogen. If the solvent vapor flow approaches 0 at the end of the first drying section, both measured values approach the same value because the nitrogen content in the

Gas flow is growing steadily and the measured value of the Pirani probe is increasingly approaching the absolute pressure measured value. The temperature of the heating / cooling plates can now be slowly increased to the temperature of the shelf and adjusted as the drying of the shelf temperature continues. The degree of approximation to the shelf temperature is e.g. determined as a function of the pressure difference between the two pressure displays.

Predictive control of the heating / cooling plates: If drying processes were recorded on the product to be dried under defined conditions in the laboratory test and this drying process was carried out using a simulation program

If all freeze-drying properties / parameters of the product have been used, if the freeze-drying properties of the freeze dryer are known, the drying process of the product can be calculated in advance and the values of the product temperature determined by the calculation program can be used as a guide for the heating / cooling plate temperatures. This method is shown in Fig. 3b.

Hybrid method: Here the product temperatures are determined from the measurements in the freeze dryer (absolute pressure, pressure after conductivity probe) and simulation calculations and used as a guide for the heating / cooling plate temperature.

The invention also relates to a method for drying moist material using a drying apparatus according to the invention, with the steps: sterilizing, optionally hot sterilizing the chamber including the unoccupied setting plates,

Load the shelves with wet goods or containers containing wet goods Closing the chamber opening and cooling of the shelves, simultaneous cooling of the heating / cooling plates, then evacuating and running through a temperature program for gradually heating the shelves and at the same time gradually adjusting the temperature of the heating / cooling plates to the temperature of the container or

Moist material,

Ventilating the device with sterile gas,

Setting the temperature of the setting plates and the heating / cooling plates to the discharge temperature, if necessary to the ambient temperature, if necessary closing the containers and removing the containers or the dry goods.

In the figures, the new freeze drying device is shown purely schematically and is explained in more detail below by way of example. Show it:

Figure 1 shows the typical structure of a freeze-drying chamber according to the invention with a condenser, setting plates and wall-integrated heating / cooling plates, which are connected to a separately controllable heating / cooling circuit and whose space between mechanically rigid, heavy wall structure and heating / cooling plates can be evacuated.

Fig. La shows a horizontal section through the freeze-drying chamber of Figure 1 with wall-integrated heating / cooling plates.

2 shows a variant of the freeze-drying chamber according to the invention with heating / cooling plates which are hung vertically in front of the stack of storage plates and are connected to a separately controllable heating / cooling circuit;

3a shows the temperature profile of containers which are at the edge or in the middle of the positioning plate with an unregulated wall temperature; 3b shows the temperature profile of the containers, which stand at the edge of the plate or in the middle of the positioning plate, with the wall temperature regulated according to the invention; 3c shows the temperature profile of the containers which are at the edge of the plate or in the middle of the positioning plate when the wall temperature is regulated in accordance with US Pat. No. 5,398,426;

4 calculations of the temperature profile in the case of marginal containers 3 arranged in the middle of the positioning plate 2.

Examples

1 shows a system of freeze-drying chamber 1 and condenser chamber 22, in which containers of product-filled containers are frozen and freeze-dried. In Fig. La container 3 on the shelf 2 in edge and

Center area indicated. The chamber 1 has two doors 11, 11a which can be opened separately and which are tightly closed. The freeze-drying chamber 1 has a two-shell structure. The heavy chamber wall construction 6 with reinforcing ribs 7 has the task of a vacuum-tight, torsionally rigid, which withstands the atmospheric pressure when the freeze-drying chamber 1 is evacuated

Offer housing for the second inner chamber 23 integrated into this. The chamber 1 is equipped with thermal insulation material 8 on its outside to prevent heat exchange with the environment. The inner freeze-drying chamber 23 is formed from the heating-cooling plates 4, which are kept at a distance from the chamber wall 6 with the aid of spacers 5, are connected in a pressure-tight manner to the chamber wall 6 via flexible sheets 9, so that the intermediate space 24 between heating / cooling plates 4 and Support wall 6 of the chamber 1 can be evacuated. The evacuation takes place via pipes 10, 12 which are connected to the main vacuum pump 21 via valves 20. The evacuation of the intermediate space 24 serves two purposes: First, the pressure equalization between the freeze-drying chamber 23 and the space 24 between the heating / cooling plates 4 and the chamber wall 6, so that pressure forces on the heating / cooling plates 4 are avoided. Secondly, it serves to lower the> heat exchanger by reducing the effective heat conduction of the intermediate space 24 as a function of pressure. During the drying phase, the pressure in the intermediate space 24 is the same as in the freeze-drying chamber 23 (p <0.1 mbar), so that the intermediate space 24 is the same evacuated gap of a dewar acts. The spacers 5 between the heating / cooling plates 4 and the chamber wall 6 are made of a poorly heat-conducting material (e.g. stainless steel), and the number of spacers 5 is minimized to the extent necessary so that the heat transfer by heat conduction through the

Spacer 5 is minimized. The connecting plates 9 are designed so that the temperature-dependent change in length of the heating / cooling plates 4 can be absorbed by the plates without any risk to the mechanical strength of the connection to the chamber wall 6. In this way, a smooth-surface freeze-drying chamber 23 is created, which can be easily cleaned. The heating / cooling plates 4 are supplied with heat transfer fluid (silicone oil) via a separately controllable temperature control system (not shown), which is supplied via line 13 and discharged via line 14. The temperature control system uses the same heat transfer medium as the shelves and can be supplied from the same storage container. The

The temperature control system for the heating / cooling plates 4 must always be operated at a temperature matched to the vial temperature, while the heat transfer medium for the setting plates 2 follows a different temperature program that follows the Lyo cycle.

The temperature program for the heating / cooling plates 4 depends on the temperature of the containers. This method has already been described in general terms above.

Example 2

FIG. 2 shows another embodiment of the freeze dryer with regard to the attachment of heating / cooling plates 4 '. Here, the temperature-controlled plates 4 'hang freely in the chamber 23. The heating / cooling plates 4' are suspended at a distance parallel to the edges of the positioning plates 2, so that space for all the organs assigned to the positioning plates 2, e.g. Hoses 25, 26 for the heat transfer medium, shelf holder (not shown), is preserved.

Known ClP / Sff devices (automatic cleaning and sterilization systems) can also be provided in the interior of the chamber. The heating / cooling plates 4 ′ are in turn fed by the heat transfer medium from a separate heat transfer circuit via inlet 13 and return 14. The mass the heating / cooling plates corresponds in both embodiments (according to example 1 and 2) to the mass of the setting plates 2, so that the heating / cooling dynamics of the plates 2 and 4 or 4 'are coordinated with one another and there are no temperature shifts due to mass inequality.

Temperature curve calculations:

For the temperature profile in different variants of the freeze drying device, calculations are carried out, which are shown in the diagrams according to FIGS. 3a to 3c and 4.

Fig. 3a shows the temperature profile of the container, the edge or in the middle of the

Stand plate, with unregulated wall temperature; herein denote the

Abbreviation: a unregulated wall temperature b place plate temperature c edge container temperature d center container temperature Here, as in the following diagrams, the indices 1 stand for the temperature at 1 mm cake height of the drying goods and indices 6 for the temperature at 6 mm cake height of the drying goods;

3b shows the temperature profile of the containers, which stand at the edge of the plate or in the middle of the positioning plate, with the wall temperature regulated according to the invention; Here the abbreviations denote: a regulated wall temperature b shelf temperature c edge container temperature d center container temperature; 3c shows the temperature profile of the containers which are at the edge of the plate or in the middle of the positioning plate when the wall temperature is regulated in accordance with US Pat. No. 5,398,426; Here the abbreviations denote: a regulated wall temperature b shelf temperature c edge container temperature d center container temperature.

The diagrams immediately show that when the device according to the invention is used with a controlled wall temperature, the temperature behavior of the containers on the edge essentially corresponds to the behavior of the containers arranged in the center on the positioning plate (FIG. 3b), while there are considerable differences in the temperature profile during operation of conventional devices occur (Fig. 3a); likewise when regulating the wall temperature in accordance with US Pat. No. 5,398,426 (3c).

FIG. 4 shows the data from an experiment in a 1 m ² pilot freeze dryer (I m ² footprint). All thin lines are measured values. The bold lines are calculated values. The temperature profiles of containers 3 that stand at the edge of the plate and the temperature profiles of containers 3 that were arranged in the center of the plate - far from the wall and protected by the neighboring containers - were compared. The calculated temperature profiles distinguish two cases:

for the vials arranged in the center, no heat transfer through the radiating wall is taken into account, for the vials positioned at the edge, the complete heat exchange with the wall is taken into account.

The wall itself is in heat exchange with the setting plates 2 and the surroundings and is therefore taken into account as changing over time. The match of calculated temperatures with the measured temperatures can be considered satisfactory if one takes into account the difficulties of measuring the temperature in the containers. From this measurement and the evaluation by the simulation program it can be deduced that the marginal containers 3 will also follow the temperature profile of the containers in the center when eliminating the driving temperature potential between the wall and the setting plates 2, as is the case in the diagram in FIG. 3b for another case was calculated; In Fig. 4, the abbreviations a to g mean: a shelf temperature b calculated wall temperature bj 23 measured wall temperatures c chamber pressure (measured) d central container temperature (measured) e central container temperature (calculated) f edge container temperature (measured) g edge container temperature (calculated).

Claims

claims

1. Drying apparatus (1) for removing solvent from moist material, consisting of at least one drying chamber (23) with at least one positioning plate (2) for receiving containers (3) filled with moist material or flat layers of moist material, the drying chamber (23) is connected to a condenser (22) via a vapor channel (15) in which the sublimed solvent can be separated, the setting plates (2) being connected to a temperature-controlled heating / cooling circuit, the chamber (23) heating / cooling plates ( 4) or (4 ') with a second

Heat transfer circuit are connected, characterized in that the heating / cooling plates (4) and (4 ') are largely thermally decoupled from the chamber wall (6).

2. Drying apparatus according to claim 1, characterized in that the heating

/ Cooling plates (4) or (4 ') are arranged at a distance from the chamber wall (6).

3. Drying apparatus according to one of claims 1 or 2, characterized in that the outer chamber wall (6) is designed to be pressure-resistant, so that the surface forces are absorbed without deformation when the chamber is evacuated.

4. Drying apparatus according to one of claims 1 to 3, characterized in that the outer chamber wall (6) has thermal insulation so that the heat exchange of the system with the environment is minimized.

5. Drying apparatus according to claim 2 to 4, characterized in that the heating / cooling plates (4) are vacuum-tightly connected to the chamber wall (6)

6. Drying apparatus according to one of claims 1 to 5, characterized in that the heating / cooling surfaces (4; 4 ') are mechanically connected to the inside of the chamber wall (6) via spacers (5) and form an evacuable flat gap with the latter , Vacuum connections are provided in the chamber wall (6).

7. Drying apparatus according to one of claims 1 to 6, characterized in that the gap is adjustable by a vacuum system to the pressure level of the drying chamber for the purpose of pressure equalization.

8. Drying apparatus according to one of claims 1 to 7, characterized in that the spacers (5) are made of poorly heat-conducting material, in particular stainless steel.

9. Drying apparatus according to one of claims 1 to 8, characterized in that elastic connecting plates (9) between the side heating / cooling plates (4; 4 ') and the chamber wall (6) are designed so flexibly that the temperature-related changes in length of the heating / Cooling surfaces can be compensated for without material damage.

10. Drying apparatus claim 1, characterized in that heating / cooling plates (4 ') are hung parallel to the edges of the setting plates (2) at a distance from the setting plates (2) in the drying chamber (1), so that the hanging Heating / cooling plates form an almost closed radiation cage around the stack of plates

11. Drying apparatus according to one of claims 1 to 10, characterized in that the drying chamber (23) can be evacuated during the freezing process to reduce the effects of convection

12. Drying apparatus according to one of claims 1 and 10, 11, characterized in that the chamber wall (6) has an external thermal insulation.

13. Drying apparatus according to one of claims 1 and 10, 11, 12, in which the

Facilities for CIP / SLP are attached so that all surfaces can be cleaned.

14. Drying apparatus according to one of claims 1 to 13, characterized in that the temperature control systems for the heating / cooling plates can be adjusted to the suitable temperature in a sensor-controlled manner.

15. Drying apparatus according to one of claims 1 to 14, characterized in that the temperature control systems for the heating and cooling plates are predictively adjustable to a suitable temperature by a computer program.

16. Drying apparatus according to one of claims 1 to 13, characterized in that the temperature control systems for the heating / cooling plates can be adjusted to the suitable temperature in a controlled manner by means of a hybrid system comprising a sensor and a computer.

17. A method for drying moist material using a drying apparatus (1) according to one of claims 1 to 16, comprising the steps of: sterilizing, optionally hot sterilizing the chamber (23) including the unoccupied setting plates (2),

Loading the shelves (2) with or containing moisture

Containers (3)

Closing the chamber opening and cooling the setting plates (2), simultaneously cooling the heating / cooling plates (4; 4 '), Subsequent evacuation and running through a temperature program for the gradual heating of the setting plates (2) and simultaneous gradual adaptation of the temperature of the heating / cooling plates (4; 4 ') to the temperature of the container (3) or the moist material, ventilation of the device with sterile gas .

Setting the temperature of the setting plates (2) and the heating / cooling plates (4; 4 ') to the discharge temperature, if necessary to the ambient temperature, if necessary closing the container (3) and removing the container (3) or the moist material.